Journal of Thoracic Oncology最新文献

Introduction: In the first interim analysis of the phase 3 ADRIATIC trial, consolidation durvalumab significantly improved overall survival and progression-free survival (primary endpoints) versus placebo in patients with limited-stage small-cell lung cancer (LS-SCLC) without disease progression after concurrent chemoradiotherapy (cCRT). We report the patient-reported outcomes.

Methods: Patients received durvalumab, durvalumab-tremelimumab, or placebo every 4 weeks for up to 24 months. Patient-reported global health status/quality of life (GHS/QoL), functioning, and symptoms, assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30/Questionnaire-Lung Cancer 13 (secondary endpoints), are reported for durvalumab and placebo only; the durvalumab-tremelimumab arm remained blinded at this analysis. Change from baseline (for prespecified key scales), time to deterioration (TTD), and improvement rates (all scales) were examined. A score change of ≥10 from baseline was considered a clinically meaningful deterioration/improvement. Analyses were not alpha-controlled.

Results: In both arms (durvalumab, n=264; placebo, n=266), mean score changes in prespecified key scales from baseline up to 24 months were small and not clinically meaningful. There were no between-arm differences in TTD except for arm/shoulder pain (longer with durvalumab versus placebo [median TTD: 25.7 versus 9.1 months; HR: 0.70 (95% CI: 0.51-0.94)]) and similar improvement rates between arms for most scales; a higher improvement rate for chest pain was observed with durvalumab versus placebo (odds ratio: 2.28 [95% CI: 1.08-4.95]).

Conclusions: Consolidation durvalumab following cCRT did not compromise patients' GHS/QoL, functioning, or symptoms versus placebo, further supporting this treatment regimen as the new standard of care for LS-SCLC.

Background: Outcomes in unresected locally advanced non-small cell lung cancer (LA-NSCLC) are poor despite improvement with immunotherapy following concurrent chemoradiation (cCRT). Although KRAS is the most common mutated oncogene in NSCLC, its impact on outcomes in LA-NSCLC treated with cCRT and durvalumab remains underexplored.

Methods: We conducted a multicenter retrospective analysis of patients with stage III non-squamous non-small cell lung cancer (non-sq NSCLC) treated with definitive cCRT followed by durvalumab. Progression-free survival (PFS) and incidence of distant metastasis and locoregional recurrence were compared by KRAS status. Of patients who underwent next generation sequencing (NGS), we assessed the impact of co-alterations on PFS.

Results: Among 208 consecutive patients, 117 were KRAS wild type (WT) and 91 were KRAS mutant. Median PFS was shorter for KRAS mutant disease compared to KRAS WT (16 vs. 28 months, p = 0.024). KRAS mutations were associated with worse PFS on univariable and multivariable analyses. There was an increased incidence of distant metastasis for KRAS mutant compared to KRAS WT disease (2-year 44% vs. 34%, p = 0.042), including increased brain metastasis incidence (p = 0.007). Among KRAS-mutant tumors, co-alterations with CDKN2A and/or STK11 were associated with worse PFS compared to KRAS WT, whereas KRAS mutations without CDKN2A or STK11 co-alterations were not.

Conclusions: KRAS mutant non-sq LA-NSCLC is associated with inferior outcomes, largely driven by increased distant and brain metastases. Tumors with concurrent CDKN2A and/or STK11 alterations had the poorest outcomes. These findings support the evaluation of KRAS inhibitors in this high-risk stage III population.

BRAF mutations are detected in approximately 3% to 8% of patients with NSCLC. In contrast to melanoma, in which most BRAF mutations occur at the V600 codon, only approximately 35% of BRAF-mutant NSCLC tumors harbor V600 mutations. Among the remaining cases, 60% to 70% present non-V600 mutations, primarily in exons 11 and 15. BRAF mutations are classified into three classes according to their kinase activity and their dependence on RAS activation. Compared with class I (V600), patients with class II and class III mutations are associated with poorer clinical outcomes partly due to the lack of effective targeted therapeutic strategies. Indeed, although dual BRAF and MEK inhibition has demonstrated clinical benefit in BRAF V600-mutant NSCLC, there is currently no consensus on treatment strategies for patients with class II and class III mutations. Beyond point mutations, other BRAF alterations (e.g., gene fusions, deletions, and amplifications) have been identified in treatment-naive tumors and in the context of acquired resistance to targeted therapies in other oncogene-driven NSCLC subtypes. However, the biology and clinical implications of these alterations remain poorly characterized. In this review, we provide a comprehensive overview on the biology, epidemiology, and therapeutic strategies of class II/III BRAF mutations, fusions, deletions, and amplifications in NSCLC. We highlight current challenges in the clinical management of BRAF-mutant NSCLC, emerging inhibitors, and combinatorial therapeutic strategies developed to treat non-V600E BRAF-driven cancers. Finally, we briefly discuss BRAF alterations in the context of resistance to targeted therapies in other oncogene-driven NSCLC.

Introduction: Effective therapies are needed for NSCLC patients with HER2 mutant tumors that progress on the HER2 antibody drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.

Methods: Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2 targeting approaches.

Results: We determined that acquired resistance to T-DXd could occur through multiple mechanisms including payload resistance which could be mediated by SFLN11 loss and copy number gains in the efflux pump ABCC1/MRP1. Moreover, T-DXd resistance could be mediated by secondary HER2 extracellular mutations in domain IV, the trastuzumab binding site. Tumor cells with acquired payload resistance or domain IV mutations maintained HER2 signaling and remained sensitive to HER2 TKIs including zongertinib or poziotinib. Likewise, patients with HER2 mutant NSCLC treated with poziotinib demonstrated similar response rates regardless of prior T-DXd.

Conclusions: In HER2 mutant NSCLC patients, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.

Introduction: Clinical guidelines recommend upfront osimertinib monotherapy for asymptomatic brain metastases (BM) in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), despite a lack of randomised trial evidence. We conducted two randomised phase II trials, OUTRUN and LUOSICNS, to evaluate the efficacy and safety of upfront stereotactic radiosurgery (SRS) plus osimertinib versus osimertinib in this patient population.

Methods: Participants with up to ten BM amenable to SRS were randomised 1:1 to SRS followed by osimertinib (80mg daily) or osimertinib monotherapy. SRS was delivered as a single or multi-fraction regimen. The primary endpoint was 12-month intracranial progression-free survival (ic-PFS). Key secondary endpoints include overall survival (OS), patterns of intracranial progression, and safety. Data from both trials were prospectively pooled for a joint analysis.

Results: Overall, 79 participants were randomised. At a median follow-up of 39.0 months, 12-month ic-PFS was not significantly different between SRS plus osimertinib (n = 39) over osimertinib monotherapy (n = 40) (11%, 95% CI, -10% to 32%, P=.31; median ic-PFS 21.9 versus 17.2 months). Median OS was 46.1 versus 29.1 months. Among those with intracranial progression, 35% in the SRS plus osimertinib group and 57% in the osimertinib monotherapy group underwent SRS at progression. Grade 3/4 radionecrosis occurred in 5% of participants treated with SRS plus osimertinib.

Conclusions: Adding upfront SRS to osimertinib did not significantly improve 12-month ic-PFS in EGFR mutant NSCLC with BM. This represents the first randomised evidence supporting the use of osimertinib monotherapy as upfront therapy in minimally symptomatic patients with low burden BM.

Introduction: The cardiovascular toxicity of radiation therapy (RT) remains incompletely understood in patients with NSCLC. Our objective was to define changes in echocardiographic parameters of structure and function with RT and their associations with cardiac dose-volume metrics.

Methods: This multicenter, longitudinal, prospective cohort study included participants with NSCLC who received standard, curative-intent thoracic RT. Dose-volume metrics were extracted from centrally contoured cardiac substructures. Echocardiograms at baseline, end of RT, 6 months post-RT, and 12 months post-RT were core laboratory-quantified. Repeated-measures multivariable linear regression via generalized estimating equations estimated changes in echocardiographic measures and associations with dose-volume metrics.

Results: Across 125 participants, there was a modest worsening in left ventricular ejection fraction (LVEF) (p = 0.019), global longitudinal strain (p < 0.001), circumferential strain (p < 0.001), and Ea/Ees (p = 0.011) post-RT that largely recovered by 12 months. Cardiac dysfunction, defined as LVEF declines of at least 10% from baseline to a threshold value of less than 50%, occurred in 7.2% of participants at a median of 1.7 months after RT initiation. Mean heart dose was associated with LVEF declines (-1.1%, 95% confidence interval: -2.2 to 0.0 per interquartile range increase, p = 0.044), as was whole heart V30 (-1.4%, 95% confidence interval: -2.5 to -0.3 per interquartile range increase, p = 0.015); with multiple comparison adjustment, whole heart V30 remained significant (p = 0.030).

Conclusions: On average, there were modest changes in cardiac function immediately after RT in patients with NSCLC, with a subset experiencing clinically relevant cardiac dysfunction. Although whole heart V30 was associated with LVEF declines, suggesting its relevance in RT planning, there is also a need for newer dose-volume measures.